The proposed research has the primary goal of beginning to translate basic and clinical research into innovative clinical assessment and therapeutics. Functional brain imaging, as well as, animal 2-deoxyglucose studies have demonstrated that antipsychotic drugs have robust effects on striatal activity. This project is a follow-up to a series of studies of ours and others that have found low relative metabolic rates in the striatum as assessed by 18-F-2-deoxyglucose positron emission tomography (FDG-PET) to predict antipsychotic response. We will acquire fMRI and sensorimotor gating (passive- and active-attention prepulse inhibition (PPI) of startle) in a large sample of unmedicated schizophrenia patients (n=64; plus an additional 16 patients to allow for 20% attrition) at baseline (Day 0) and at the end of a 4-week risperidone treatment trial. Using fMRI, this project will extend earlier FDG-PET studies which showed low dorsal caudate activity predicts antipsychotic response. We will also obtain fMRI and PPI measures in a healthy-control group (n=32; plus 3 for attrition) as a benchmark for comparing whether caudate and PPI activity is more normalized with risperidone treatment in the responder subgroup compared with the treatment non-responder subgroup. Our pilot data suggest that PPI measures are a potential proxy for caudate function and may eventually serve as useful intermediary treatment predictors. We also have new pilot data indicating that low caudate activity measured with fMRI and poor PPI show a trend for predicting better response to a 4-week risperidone trial in schizophrenia patients. We anticipate that this project will take four years: three months for startup, 39 months for patient and healthy control comparison group acquisition, and 6 months for data analysis and writing scientific manuscripts. The project will be conducted at the James J. Peters VA Medical Center and involve patients recruited from three sites: the James J. Peters and New York Harbor VA Medical Centers, and Mount Sinai Hospital (J.J. Peters VAMC affiliate). Approximately two-thirds of the patient sample will be recruited, diagnosed and treated at the J.J. Peters VAMC. One-third of the patient sample will be recruited from the NY Harbor VAMC and patients from Mount Sinai will be recruited for attrition purposes only. Healthy controls will be recruited from the James J. Peters VAMC. The fMRI and psychophysiological testing sessions will take place at Mount Sinai for all study participants where a state-of-the-art head-dedicated 3T MRI scanner and the Cognitive Psychophysiology Laboratory are located. The primary objective of the proposed research is to begin to identify potential biomarkers for predicting antipsychotic treatment response in patients with schizophrenia. Currently, there is no biological marker to assist psychiatrists in determining which antipsychotic medication will give the optimal response in a given patient. Instead, the selection of an antipsychotic medication for a particular patient involves a complex trial- and-error process. Demonstration of the usefulness of caudate and sensorimotor gating measures as biomarkers for predicting treatment response in schizophrenia patients could bring ecologically-valid tools from bench to bedside.